The primary goals of this competitive renewal program project proposal are to establish a better physiologic understanding of cardiac disease and to design more rational approaches to therapy. Many new drugs and surgical techniques become available almost daily for treating patients with heart disease. The objectives of this program for evaluating these forms of therapy include: investigation of the mechanism of action of drugs and surgical therapy for heart disease; development of a better understanding of how treatment alters the pathophysiology and natal history of heart disease; development of cellular and animal models simulating cardiac states where drug actions can be studied precisely; establishment of interrelationships between biochemical actions of drugs and their physiologic actions; determination of the pathophysiologic principles necessitating surgical or drug therapy for a number of cardiac disorders; documentation of the efficacy of therapy in some cardiac disorders; and, assessment of the interactions between the many pharmacologic agents administered to a single cardiac patient. The interrelationships between dosage regimen and the resulting blood levels with hemodynamic, electrophysiologic, and clinical effects and their dynamics will be investigated. New computer techniques for evaluating cardiac performance longitudinally will be developed and validated. The drug groups which will be assessed include antiarrhythmic agents, cardiac glycosides, inotropic agents, adrenergic blocking drugs, and analgesics. Emphasis will be placed on the pharmacokinetic principles which can be applied in disease states which alter physiology, such as lowered cardiac output. The overall goal of this program is to establish an improved and rational pharmacologic and physiologic basis for the treatment of many types of heart disease.